Process for the preparation of 17alpha, 21-di-hydroxy 3, 11, 20-triketo-allopregnane-21-acylate



2,988,556 PROCESS FOR THE PREPARATION OF 17a,21-DI- HYD XY 3,11,20- TO-ALLOPREGNANE- R ZI-ACYLATE Jacobus Simon Favier, Heesch, Netherlands, assignor to Organon Inc., Orange, N.J., a corporation of New Jersey No Drawing. Filed Sept. 21, 1959, Ser. No. 841,029 Claims priority, application Netherlands Oct. 10, 1958 Claims. (Cl. 260-397.45)

The invention relates to the preparation of 17a,21-dihydroxy-3,11,ZO-triketo-allopregnane-Zl-acylate from the corresponding 3p-hydroxy compound by oxidation with a N-halogenated carboxylic amide or carboxylic imide in a tertiary alcohol and in the presence of'an acid-binding It is known from the article of Th. H. in J. Am. Chem. Soc., vol.

corresponding 3-keto compound by means of N-bromo acetamide or N-bromo succinimide in the presence of tbutanol and pyridine.

A similar oxidation of a 3 8-hydroxy-pregnane compound of the allo No. 744,981. The conversion disclosed the oxidation of the 35,11a,1711,21-tetrahydroxy-20-ketoallopregnane-Zl-acetate to the corresponding 3,1l-diketo compound by means of N-bromo acetamide in the presence of pyridine.

It has appeared that this known oxidation method applied to the 3/5,l7a,21-trihydroxy-11,20-diketo-allopregnane-Zl-acylate, gives considerably lower yields of the corresponding 3-keto compound than when start is made from the 3a-hydroxy-pregnane compound of the normal series. case the yield of the oxidation in question is only about 70%.

It Was now surprisingly found genated aliphatic hydrocarbon.

According to the invention the 17a,21-dihydroxy-3,l1,

20-triketo-allopregnane-Zl-acylate is prepared from the 3B,17oz,21 trihydroxy 11,20 di-keto allopregnane ing agent, and a halogenated aliphatic hydrocarbon.

e ester grouping present in 21-position of the starting product may be derived both from an aliphatic, aromatic, and from an araliphatic carboxylic acid.

In general start is made from the 21-acetate of the present compound.

As examples of N-halogenated carboxylic imides or amides to be applied are mentioned: N-bromo-acetamide, N-chloro-acetamide, N-bromo-phthalimide, N-bromo-succinimide and N-chloro-succinimide.

Preferably N-bromo-succinimide is used.

As acid-binding agents can be used for example picoline, collidine, pyridine, toluidine, quinoline, or N-dimethyl-aniline. Preferably pyridine is used.

T-butanol or t-amyl alcohol is usually applied as tertiary alcohol.

bromoform, carbon tetrachloride, dichloro butane, bromobutane, and the like. It is to be preferred a halogenated saturated aliphatic hydrocarbon I 6 carbon atoms, in which are to be considered chloroform and methylene chloride.

The oxidation according to the invention is usually Carried out in such a manner that the compound to be per mol of steroid.

T e thus prepared reaction mixture is allowed to react for a certain time dependent on the reaction temperature.

example, it is possible to convert this compound in one reaction step into the prednisone-Zl-acylate by means of selenium dioxide.

The following examples illustrate the invention.

Example I sulphite in water. ice-water, after which the chloroform layer is separated. dilute sodium 1 N sulphurwater, dried on sodium sulphate, and The residue is recrystallized from acetone, yielding 38 g. of 17a,21-dihY- droxy3,ll,ZO-triketo-allo-pregnane-Zl-acetate, or 85%, of melting-point of from 223228 C.; [a] (acetone). In analogous manners also the ZI-butyrate and 21- phenyl propionate of the oxidized to the yield of resp.

corresponding 3-keto Example I] compounds in a Example III 30 g. of 3,8,17ot,21-trihydroxy-11,20-diketo-allopreg nane-Zl-acetate are dissolved, while heating, in a mixture of 50 ml. of N-dimethyl aniline, 385 ml. of t-amyl alcohol, and 420 m1. of carbon tetrachloride. Then the mixture is cooled to 20 C., after which 48 g. mophthalimide are added, while stirring. The reaction mixture is left to stand at 20 C. for 24 hours, after which it is processed as described in Example I. Ob-

present compound have been tained is the 17,21 dihydroxy 3,11,20 triketo allopregnane-Zl-acetate in a yield of 82%.

I claim:

1. Process for the preparation of 17u,21-dihydroxy-3, 11,ZO-triketo-allopregnane-Zl-acylate comprising reacting 3B,l7'a,2l trihydroxy 11,20 diketo allopregnane 21-acylate with a compound selected from the group consisting of N-bromo succinirnide, N-bromo-acetamide and N-bromo-phthalimlde and in the presence of a tertiary alcohol selected from the group consisting of t-butanol and t-amyl alcohol, a tertiary amine and a phatic hydrocarbon.

2. Process for the preparation of 17a,21-dihydroxy- 3,11,20-triketo-allopregnane-Zl-acylate comprising reacting 343,17 a,21 trihydroxy-l1,20-diketo-allopregnane- ZI-acylate with a compound selected from the group consisting of N-bromo-succinimide, N-bromo-acetamide and N-bromo phthalimide and in the presence of a tertiary alcohol selected from the group consisting of t-butanol and t-amyl alcohol, a tertiary amine and a halogenated saturated aliphatic hydrocarbon with 1 to 6 carbon atoms.

3. Process for the preparation of 17a,21-dihydroxy-3, 11,ZO-triketo-allopregnane-Zl-acylate comprising reacting 3B,17a,2l trihydroxy 11,20 diketo allopregnane 21-acylate with a compound selected from the group consisting of N-bromo-succinimide, N-bromo-acetamide and N-bromo-phthalimide and in the presence of a tertiary alcohol selected from the group consisting of t-butanol and t-amyl alcohol, a tertiary amine and chloroform.

4. Process for the preparation of 17a,21'-dihydroxy-3, 11,20-triketo-allopregnane-2l-acylate comprising reacting 3B,17a,21 trihydroxy 11,20 diketo allopregnane-21-acylate with a compound selected from the group consisting of N-bromo-succinimide, N-bromo-acetamide and N-bromo-phthalimide and in the presence of a tertiary alcohol selected from the group consisting of t-butanol and t-amyl alcohol, a tertiary amine and methylene chloride.

References Cited in the file UNITED STATES PATENTS of this patent 20 2,691,029 Hanze et al. Oct. 5, 1954 2,714,599 Fonken et al. Aug. 2, 1955 2,773,079 Djerassi et a Dec. 4, 1956 2,843,611 Fonken July 15, 1958 

1. PROCESS FOR THE PREPARATION OF 17A,21-DIHYDROXY-3, 11,20-TRIKETO-ALLOPREGNANE-21-ACYLATE COMPRISING REACTING 3B,17A,21 - TRIHYDROXY - 11,20 - DIKETO - ALLOPREGNANE21-ACYLATE WITH A COMPOUND SELECTED FROM THE GROUP CONSISTING OF N-BROMO SUCCINIMIDE, N-BROMO-ACETAMIDE AND N-BROMO-PHTHALIMIDE AND IN THE PRESENCE OF A TERTIARY ALCOHOL SELECTED FROM THE GROUP CONSISTING OF T-BUTANOL AND T-AMYL ALCOHOL, A TERTIARY AMINE AND A HALOGENATED ALIPHATIC HYDROCARBON. 